Adenosine is a nucleoside that occurs naturally in mammals, which acts as a ubiquitous biochemical messenger. The heart, for instance, produces and releases adenosine in order to modulate heart rate and coronary vasodilation. Likewise, adenosine is produced in the kidney to modulate essential physiological responses, including glomerular filtration rate (GFR), electrolyte reabsorption, and renin secretion.
Adenosine is known to bind to and activate seven-transmembrane spanning G-protein coupled receptors, thereby eliciting a variety of physiological responses. There are 4 known subtypes of adenosine receptors (i.e., A1, A2A, A2B, and A3), which mediate different, and sometimes opposing, effects. For example, activation of the adenosine A1 receptor, elicits an increase in renal vascular resistance, which leads to a decrease in glomerular filtration rate (GFR), while activation of the adenosine A2A receptor elicits a decrease in renal vascular resistance. Conversely, blockade of the A1 adenosine receptor decreases afferent arteriole pressure, leading to an increase in GFR and urine flow, and sodium excretion. Furthermore, A2A adenosine receptors modulate coronary vasodilation, whereas A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See, Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153 and Ralevic, V. and Burnstock, G. (1998), Pharmacological Reviews, Vol. 50: 413-492), and A3 adenosine receptors modulate cell proliferation processes. Two receptor subtypes (A1 and A2A) exhibit affinity for adenosine in the nanomolar range while two other known subtypes A2B and A3 are low-affinity receptors, with affinity for adenosine in the low-micromolar range. A1 and A3 adenosine receptor activation can lead to an inhibition of adenylate cyclase activity, while A2A and A2B activation causes a stimulation of adenylate cyclase.
It has been shown that adenosine, acting at specific cell surface receptors, has the potential to suppress inflammation and that inflammation itself may increase extracellular adenosine levels (Cronstein, et al., 1986, Journal of Clinical Investigation 78:760-770; Cronstein, et al., 1983, Journal of Experimental Medicine 158:1160-1177). Further, it has been demonstrated that adenosine mediates the anti-inflammatory effects of low-dose methotrexate therapy for Rheumatoid Arthritis (Reviewed in Cronstein, 2005, Pharmacol Rev 57:163-172). Exploration of the therapeutic and toxic properties of methotrexate in the treatment of RA has led to a number of other potentially important pre-clinical therapeutic developments. Methotrexate increases giant cell formation from peripheral blood monocytes and that this effect is mediated by adenosine acting at A1 receptors (Merrill, et al., Arth. Rheum. 40:1308-1315). In addition, A2A receptor antagonists promote giant cell formation by diminishing the effect of endogenous adenosine although the A1 receptor-mediated promotion of giant cell formation appears to dominate.
A1 receptor antagonists completely block, in a dose-dependent fashion, osteoclast formation. Similarly, the A1 receptor antagonists block osteoclast function (resorption of dentin). Six-month old A1 KO mice demonstrate increased bone density. Their bones demonstrate diminished resorption, and some evidence indicates that the osteoclasts in the A1 knockout mice do not resorb bone. A murine model of post-menopausal osteoporosis, ovariectomy-induced bone loss, reveals that treatment of mice with an adenosine A1 receptor antagonist completely prevents ovariectomy-induced bone loss. Adenosine A1 receptors may be useful in treating and preventing osteoporosis.
Replacement of osteoarthritic or damaged hips and knees is among the most common surgical procedures performed in the United States and other developed countries. Excellent results are achieved in more than 95% of patients. Prosthodontic prostheses are also increasingly successful as well. However, aside from infectionm the most pressing difficulty in maintaining mobility is the development of bone resorption and loosening of the prosthesis leading to early reimplantation. There are two components to the bone resorption including an inflammatory reaction to debris from the prosthesis (ultra high molecular weight polyethylene debris). However, inflammation alone is not sufficient to induce bone resorption. Differentiation and stimulation of osteoclasts is required for the destruction of peri-prosthetic bone and bone loosening.
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